We have observed that distinct phenotypic subsets of antigen-specific CD4 Th1 T-cells develop in response to viral infection. Although both of these subsets have a Th1 phenotype (they express T-bet, IFNg, TNFa, and IL-2), they differ with respect to their expression of several co-stimulatory molecules such as TRANCE, CD30L, and CD40L(CD154). In addition, they differ with respect to the production of the proinflammatory cytokine IL-21. As a result of these differences, we hypothesize that each of these antigenspecific CD4 Th1 subsets have specialized abilities to provide help to B-cells and CDS T-cells. These initial observations were made using the mouse LCMV infectious model. We plan to extend them by determining if each of the antigen-specific CD4 Th1 subsets develop in response to other viral and bacterial infections such as VSV, vaccinia, influenza, and listeria. Our main focus will be to more fully understand the development and functional activities of each subset. Our specific aims are to: 1.) determine the lineage relationship between the subsets, 2.) determine if the subsets have distinct roles in B-cell help, and 3.) determine if each subset makes different contributions to CDS T-cell help. These findings and proposed experiments are important in the context of transplantation because: 1.) immunity generated by heterologous viral infections increases the number of cross-reactive memory T-cells that can respond to alloantigen, and 2.) memory T-cells have different requirements for co-stimulation than naTve T-cells. The information gained from addressing these specific aims will provide rationale for improving current co-stimulation blockade treatments to induce tolerance of allograft transplants. In addition, it will provide important insight for the design of safer and more effective vaccines. This research is important to public health because it will help us understand how our immune system can be specifically manipulated to improve tolerance of organ transplants and to provide better protection against infectious diseases.